Targeting complement components C3 and C5 for the retina: Key concepts and lingering questions

Prog Retin Eye Res. 2021 Jul:83:100936. doi: 10.1016/j.preteyeres.2020.100936. Epub 2020 Dec 13.


Age-related macular degeneration (AMD) remains a major cause of legal blindness, and treatment for the geographic atrophy form of AMD is a significant unmet need. Dysregulation of the complement cascade is thought to be instrumental for AMD pathophysiology. In particular, C3 and C5 are pivotal components of the complement cascade and have become leading therapeutic targets for AMD. In this article, we discuss C3 and C5 in detail, including their roles in AMD, biochemical and structural aspects, locations of expression, and the functions of C3 and C5 fragments. Further, the article critically reviews developing therapeutics aimed at C3 and C5, underscoring the potential effects of broad inhibition of complement at the level of C3 versus more specific inhibition at C5. The relationships of complement biology to the inflammasome and microglia/macrophage activity are highlighted. Concepts of C3 and C5 biology will be emphasized, while we point out questions that need to be settled and directions for future investigations.

Keywords: Age-related macular degeneration; C3; C5; Complement; Geographic atrophy; Retina.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Complement Activation
  • Complement C3*
  • Complement C5*
  • Geographic Atrophy*
  • Humans
  • Macular Degeneration*
  • Retina


  • Complement C3
  • Complement C5